Calcium is the most abundant and one of the most important minerals in the human body. Calcium is also an important cation in a wide variety of biological functions such as clotting of blood, the maintenance of normal heart beat and the initiation of neuromuscular and metabolic activities. The skeletal system provides an important reservoir for blood calcium in these processes. More than 99 percent of the calcium in the body is present in the skeleton as hydroxyapatite. Various diseases and metabolic disorders can cause the level of serum calcium to increase or decrease and thus cause serious biochemical and clinical abnormalities.
Of the factors which control calcium and skeletal metabolism, two polypeptide hormones, parathyroid hormone and calcitonin, are considered to be the most important. Parathyroid hormone (PTH) is an 84-amino acid peptide that acts to raise blood calcium and increase bone resorption. Calcitonin is a 32-amino acid polypeptide that acts to decrease bone resorption and lower blood calcium. Calcitonin is produced in the thyroid gland and perhaps at extra thyroidal sites and parathyroid hormone is produced in the parathyroid glands. The half life of calcitonin and of parathyroid hormone in the human body can be measured in minutes.
Hypercalcemia is defined as an excessive quantity of calcium in the blood. Hypercalcemia can occur as a result of numerous different clinical conditions, wherein there are produced high concentrations of free calcium ions in the circulating blood. Causes of hypercalcemia can include, for example, hyperparathyroidism, cancer (with or without bone metastasis), hypervitaminosis D, sarcoidosis, thyrotoxicosis, immobility, and adrenal insufficiency, among others.
Many of the manifestations of hypercalcemia are not specific to the underlying cause. Extreme hypercalcemia leads to coma and death. Neurologic manifestations in less severe cases may include confusion, lethargy, weakness, and hyporeflexia. Hypercalcemia may be detected by shortening of the QT interval on the electrocardiogram. Arrhythmias are rare, but bradycardia and first-degree heart block have been reported. Acute hypercalcemia may be associated with significant hypertension. Gastrointestinal manifestations include constipation and anorexia; in severe cases, there may be nausea and vomiting. Acute pancreatitis has been reported in association with hypercalcemia of various causes. Hypercalcemia interferes with antidiuretic hormone action, thereby leading to polyuria and polydipsia. Reversible reduction in renal function associated with significant hypercalcemia is secretion and action. The active metabolite of vitamin D, 1,25(OH).sub.2 D (dihydroxycholecalciferol), suppresses both secretion and synthesis of PTH. Reduction in 1,25(OH).sub.2 D is a major factor contributing to increased PTH secretion in renal failure.
Present treatments for hypercalcemia include vigorous intravenous hydration with diuresis to purge calcium from a patient's body. Furthermore, glucocorticoids are also occasionally used in conjunction with such intravenous hydration with diuresis to purge calcium from a patient's body. Other methods which have been utilized to treat hypercalcemia include administering Mithramycin (a chemotherapeutic agent directly toxic to tumor cells and which can decrease plasma calcium levels), administering calcitonin (a hormone from the thyroid which can inhibit bone resorption and thus decrease plasma calcium levels), Etidronate (a chemical compound which binds to calcium phosphate surfaces and inhibits crystal resorption of bone) and administering phosphate. Treatment results with each of the above discussed methods are relatively short lived, and as a consequence, hypercalcemia often readily returns after each of the above discussed treatments are discontinued.